FDA Approves Oral Factor B Inhibitor for Paroxysmal Nocturnal Hemoglobinuria

The FDA approved iptacopan (Fabhalta) as the first oral monotherapy for adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare but potentially fatal disorder affecting red blood cells (RBCs), Novartis announced.

A factor B inhibitor, iptacopan controls RBC destruction (hemolysis) by inhibiting the immune system’s alternative complement pathway. Currently available anti-C5 therapies require infusions and may not control PNH symptoms. Many patients have persistent anemia associated with anti-C5 treatment and require blood transfusions.

“An efficacious oral treatment with a demonstrated safety profile could be practice changing for physicians and help relieve burdens experienced by people with PNH,” said Vinod Pullarkat, MD, of City of Hope in Duarte, California, in a company statement. “In clinical studies, iptacopan was superior to anti-C5s in hemoglobin improvement in the absence of RBC transfusion and transfusion avoidance rate and also effective in complement inhibitor-naive individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions.”

Driven by a genetic mutation, PNH occurs in one to five individuals per million. Premature breakdown of red cells can cause symptoms that include fatigue, weakness, pallor, dyspnea, and tachycardia. Affected individuals might also have an increased risk of infection because of PNH-associated leukopenia. PNH increases a person’s risk of developing certain types of leukemia.

Principal support for the approval came from the phase III APPLY-PNH trial involving patients with residual anemia despite prior anti-C5 treatment. Additional support came from the single-arm phase III APPOINT-PNH trial in patients with no prior exposure to C5 inhibitors.

Results at 24 weeks showed that 82.3% of patients with prior anti-C5 therapy had a sustained hemoglobin increase ≥2 g/dL from baseline versus 0% in those who continued C5 inhibition (P<0.0001). Three-fourths of patients with no prior anti-C5 treatment achieved the same outcome.

Two-thirds of C5-treated patients maintained a hemoglobin level ≥12 g/dL without RBC infusions versus 0% of the patients who continued anti-C5 therapy (P<0.0001). Transfusion-avoidance rates were 95.2% with iptacopan versus 45.7% with continued anti-C5 treatment (P<0.0001).

In the APPLY-PNH trial, the most commonly reported (≥10%) adverse events (AEs) with iptacopan and anti-C5 agents were headache (19% vs 3%), nasopharyngitis (16% vs 17%), diarrhea (15% vs 6%), abdominal pain (15% vs 3%), bacterial infection (11% vs 11%), nausea (10% vs 3%), and viral infection (10% vs 31%). In the APPOINT-PNH trial, the most commonly reported AEs with iptacopan were headache (28%), viral infection (18%), nasopharyngitis (15%), and rash (10%).

Correction: This story has been updated to include the correct transfusion-avoidance rates in patients who continued anti-C5 treatment.

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